1. Field of the Invention
The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides substituted 2-methylbenzimidazole derivatives for the treatment of respiratory syncytial virus infection.
2. Background Art
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infection in infants, children, elderly and immunocompromised persons. A severe viral infection may require hospitalization for bronchiolitis or pneumonia and in some cases the viral infection is fatal. (JAMA, 1997, 277, 12). Currently only Ribavirin is approved for the treatment of this viral infection. Ribavirin is a nucleoside analogue which is administered intranasally as an aerosol. The agent is quite toxic, and its efficacy has remained controversial. RespiGam, approved for prophylaxis in high risk pediatric patients, is an intravenous immunoglobulin which effectively neutralizes the virus. Recently, Synagis, a monoclonal antibody administered through intramuscular injection has also been approved for use in high risk pediatric patients. However, both drugs are very expensive. Accordingly, inexpensive, safe and effective antiviral agents against respiratory syncytial virus will be beneficial for patients.
Many agents are known to inhibit respiratory syncytial virus (De Clercq, Int. J. Antiviral Agents, 1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1, 1998) disclosed that Ceterizine, a known antihistamine, exhibited anti-RSV activity. Tidwell et al., J. Med. Chem. 1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982), and Dubovi et al., Antimicrobial Agents and Chemotherapy, 1981, 19, 649, reported a series of amidino compounds with the formula shown below as inhibitors of RSV. 
Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of 6-aminopyrimidones that possess anti-viral activity against RSV. 
Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P. R. Wyde et al. (Antiviral Res. 1998, 38, 31) disclosed a series of triazine containing compounds that were useful for the treatment and/or prevention of RSV infection. 
In addition, T. Nitz, et al., (WO Patent, WO 00/38508, 1999) disclosed a series of triaryl containing compounds that were useful for the treatment and/or prevention of RSV and related pneumoviral infections. 
Moreover, Yu et al. (WO 020004900) also disclosed a series of substituted benzimidazoles that is useful for the treatment and prevention of RSV infection. 
A related series of compounds were first disclosed by F. Pagani and F. Sparatore in Boll Chim Farm. 1965, 104, 427 and by G. Paglietti, et al. in II Farmaco, Ed. Sci. 1975, 30, 505, and found to possess analgesic and anti-arrhythmic activity. The structural formula for these compounds are depicted in Formula Ia and Ib. 
In Formula Ia and Ib, A is —(CH2)n—N(R)2, n=2 or 3, R=Me or Et, or A is B=H, Cl, CF3, CH3CO, NO2.
Another series of closely related compounds that Sparatore had disclosed were in II Farmaco Ed. Sci. 1967, 23, 344 (U.S. Pat. No. 3,394,141, 1968). Some of the compounds were reported to have analgesic, anti-inflammatory or anti-pyretic activities. The structure of these compounds is depicted in Formula Ic. In Formula Ic, C=H, CF3, or NO2. D is —(CH2)n—NR2, n=2 or 3, R=Me or Et, or D=E is H, Cl or OEt. 
Another series of compounds structurally related to this invention are pyrido[1,2-a]benzoazoles and pyrimidio[1,2-a]benzimidazoles disclosed by S. Shigeta et al in Antiviral Chem. & Chemother. 1992, 3, 171. These compounds have demonstrated inhibition of orthomyxovirus and paramyxovirus replication in HeLa cells. The structures of these compounds are shown in Formulas Id and Ie, in which F=NH, S, or O; Q=—NHCOPh, —COOH, COOEt, or CN; T=COMe, CN, or COOEt; G=O or NH. 
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al. J. Med. Chem. 1972, 15, 655).
A series of 2-aminobenzimidazoles have been reported by E. Janssens, et al. as inhibitors of RSV in a series of recent publications and representative examples (Formula 1f-1h) are shown below from PCT WO 01/00611 A1; PCT WO 01/00612 and PCT WO 01/00615, respectively all published on Jan. 4, 2001. 
A series of triazole containing compounds have been reported by Janssen as inhibitors of RSV in PCT WO 01/36395 (May 25, 2001) and a representative example (Formula Ii) is shown below. 
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al. J. Med. Chem. 1972, 15, 655. 
Other structurally related compounds are bis-benzimidazoles which possess antifungal activity (B. Cakir, et al. Eczacilik Fak. Derg. 1988, 5, 71). 
Also, H. R. Howard et al. reported a series of benzimidazolone-1-acetic acids that possessed aldolase reductase inhibitory activity (Eur. J. Med. Chem. 1992, 27, 779-789). 
Other prior art related to the chemical structure of the present invention:    (1) F. Sparatore, et al, “Derivati Benzotriazolici Attivi Sull'accrescimento Delle Piante,” II Farmaco Ed. Sci. 1978, 33, 901.    (2) Katritzky, A. R. et al, “Synthesis and Transformations Of Substituted Benzazolyl- and Tetrazolyl(benzotriazol-1-yl)methanes,” J. Heterocyclic Chem. 1996, 33, 1107.    (3) Terri A. Fairley, et al. “Structure, DNA Minor Groove Binding, And Base Pair Specificity of Alkyl and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles), J. Med. Chem. 1993, 36, 1746.    (4) R. K. Upadhyay et al, “New Synthesis and Biological Evaluation,” Indian J. Heterocyclic Chem. 1994, 4, 121.    (5) A. R. Katritzky, et al, “A New Route to N-substituted Heterocycles,” Tetrahedron, 1993, 49, 2829.    (6) K. Yu et al. in Substituted Benzimidazole Anti-viral Agents, PCT WO00/04900 published Feb. 3, 2000.